Our long-term goal is to develop passive immunization against maternal HIV transmission during birth and through breast milk. Using combinations of human neutralizing monoclonal antibodies (nmAbs) directed against conserved HIVEnv epitopes, we showed strong synergy that resulted in potent neutralization of primary HIV isolates, including non-cladeB strains. Our primate studies were also encouraging: passive immunization with a triple mAb combination completely protected all neonatal monkeys challenged orally with simian-human immunodeficiency virus (SHIV)encoding HIV-IIIB env. Next, we orally challenged 4 neonatal macaques with pathogenic SHIV896P after passive immunization with a triple mAb combination. One infant remained uninfected, and two others were protected from acute CD4 v T-cell loss. In contrast, all 4 untreated controls had high viral loads and acute CD4 v T-cell depletion. Passive immunization with a quadruple mAb combination was then given 1 hour after oral SHIV89.6P challenge to 4newborn monkeys and again on day 8; the mAbs were given intravenously. Two out of four infants remained uninfected, and the others maintained normal CD4 v T cells. Given these data, we propose to address the following questions: 1. Can the nmAb treatment be simplified to be practical in developing countries? Can a single intra-muscular nmAb treatment provide protection as post-exposure prophylaxis against oral SHIV89.6P challenge (Specific Aim #1)? 2. Is there cross-clade neutralization in vivo? We will generate a SHIV that encodes env of a primary HIV clade A strain isolated from a newly infected African infant. The resulting chimera will be passaged rapidly in rhesus macaques, and the monkey-adapted virus, termed SHIVenvAP, will be titrated orally in macaque infants. Human neutralizing mAbs, raised initially against HIV clade B, wilt be then tested for their ability to protect newborn monkeys against oral SHIVenvAP challenge (Specific Aim #2). 3. Can passive immunization with human nmAbs lower viral load and improve clinical outcome in established SHIV infection (Specific Aim #3)? 4. Can prophylactic administration of a quadruple human mAb combination protect older infant monkeys against oral SHIV env AP challenge (Specific Aim #4)? This experiment models milk-borne HIV transmission later in infancy. These experiments are designed to evaluate the efficacy of human nmAbs against mucosal virus exposure, as it is thought to occur during intrapartum HIV transmission. Simultaneously, the experiments also test whether passive immunization represents an effective, novel approach to protect infants against virus exposure through breast-feeding. Our focus on a chimeric virus that encodes the env gene of a primary, recently transmitted African clade A isolate serves as a proof-of-concept experiment that may form the basis for subsequent clinical trials in Africa, especially against milk-borne HIV clade A transmission.